Jeremy R. Coyle

A Randomized, Placebo-Controlled Trial of Sustained-Release Dextroamphetamine for Treatment of Methamphetamine Addiction

Sixty treatment‐seeking individuals with methamphetamine (MA) dependence entered a randomized, placebo‐controlled, double‐blind clinical trial of oral dextroamphetamine (d‐AMP) as a replacement therapy for MA dependence. The subjects took 60 mg sustained‐release d‐AMP for 8 weeks, during which time they received eight 50‐min sessions of individual psychotherapy. Adverse events and urine toxicology for MA were assessed two times a week. There were no serious adverse events. Urine samples containing <1,000 ng/ml of MA were classified as negative for MA. The MA‐negative scores in the d‐AMP group (3.1 ± SD 4.6) were no higher than those in the placebo group (3.3 ± SD 5.3; P > 0.05). However, withdrawal and craving scores were significantly lower in the d‐AMP group (P < 0.05 for both). Although subjects taking d‐AMP did not reduce their use of MA, the significant reductions observed in withdrawal and craving scores in this group support the need for further exploration of d‐AMP as a pharmacologic intervention for MA dependence, possibly at higher doses.

Lack of effect of sublingual salvinorin A, a naturally occurring kappa opioid, in humans: a placebo-controlled trial.

RationaleSalvinorin A (SA) is a highly selective kappa opioid receptor agonist and the putative psychoactive compound in Salvia divinorum (SD), an increasingly abused hallucinogenic plant.ObjectivesThe objectives of this study were to characterize the physiological and subjective effects of SA versus placebo and measure drug and metabolite levels.MethodsSublingual SA doses up to 4xa0mg were administered in dimethyl sulfoxide/polyethylene glycol 400 solution to eight SD-experienced subjects using a placebo-controlled ascending-dose design.ResultsNo dose of SA produced significantly greater physiological or subjective effects than placebo. Furthermore, effects did not resemble reported “typical” effects of smoked SD. SA was detectable in plasma and urine, but was, in most cases, below the reliable limit of quantification (0.5xa0ng/mL).ConclusionsOur results suggest that the sublingual bioavailability of SA is low. Higher doses, alternate formulations, or alternate routes of administration will be necessary to study the effects of SA in humans.

Abnormal visual experiences in individuals with histories of hallucinogen use: A web-based questionnaire

Despite longstanding reports of prolonged or reoccurring perceptual changes in a subset of hallucinogen users, very little is known about Hallucinogen Persisting Perception Disorder and related visual abnormalities in hallucinogen users. We used an online questionnaire to document the symptoms and relationship to drug use of unusual visual phenomena in hallucinogen users. 16,192 individuals viewed the information sheet and 2679 were included in the study. Of these, 224 reported having unrelated diagnoses associated with unusual visual experiences and were excluded from main analyses. Most (60.6%) of the remaining 2455 participants reported having experienced drug-free visual experiences that resembled hallucinogen effects. Probability of experiencing constant or near-constant symptoms was predicted by greater past exposure to specific hallucinogens, including lysergic acid diethylamide (LSD). Although symptoms were common, few (104, or 4.2% of the sample) found them distressing or impairing enough to consider seeking treatment. Visual changes in hallucinogen users may be more common than previously suspected and are worthy of further study.

A simple, novel method for assessing medication adherence: capsule photographs taken with cellular telephones.

Objectives:Medication nonadherence is an important factor in clinical practice and research methodology. Although many methods of measuring adherence have been investigated, there is as yet no “gold standard.” We compared the usefulness and accuracy of a novel measure of adherence, photographs taken by cellular telephones with 2 incumbents: capsule count and the Medication Event Monitoring System (MEMS). Method:Twenty subjects participated in a clinical trial of the efficacy of modafinil for the treatment of methamphetamine dependence. Subjects were issued cell phones and medication in MEMS Cap equipped bottles and were instructed to take 1 capsule a day for 8 weeks, recording adherence with both systems. Pill counts were recorded at weekly inpatient visits. Subjects were paid for participation and for each capsule photograph and the returned medication bottle with MEMS Cap. Results:Capsule count-indicated adherence (proportion of prescribed medication taken) was 94.9%. When compared with capsule count, the novel method was found to underestimate adherence, whereas MEMS overestimated adherence. By using the dosing time data collected, we determined that subjects who dosed at a consistent time daily were more likely to adhere to the prescribed regimen. We also detected discrepancies in the timestamps recorded by MEMS. Conclusions:Capsule photographs are a useful measure of adherence, allowing more accurate time measures and more frequent adherence assessment than MEMS or capsule count. Given the ubiquity of cellular telephone use, and the relative ease of this adherence measurement method, we believe it is a useful and cost-effective approach.

Investigating the Mechanisms of Hallucinogen-Induced Visions Using 3,4-Methylenedioxyamphetamine (MDA): A Randomized Controlled Trial in Humans

Background The mechanisms of drug-induced visions are poorly understood. Very few serotonergic hallucinogens have been studied in humans in decades, despite widespread use of these drugs and potential relevance of their mechanisms to hallucinations occurring in psychiatric and neurological disorders. Methodology/Principal Findings We investigated the mechanisms of hallucinogen-induced visions by measuring the visual and perceptual effects of the hallucinogenic serotonin 5-HT2AR receptor agonist and monoamine releaser, 3,4-methylenedioxyamphetamine (MDA), in a double-blind placebo-controlled study. We found that MDA increased self-report measures of mystical-type experience and other hallucinogen-like effects, including reported visual alterations. MDA produced a significant increase in closed-eye visions (CEVs), with considerable individual variation. Magnitude of CEVs after MDA was associated with lower performance on measures of contour integration and object recognition. Conclusions/Significance Drug-induced visions may have greater intensity in people with poor sensory or perceptual processing, suggesting common mechanisms with other hallucinatory syndromes. MDA is a potential tool to investigate mystical experiences and visual perception. Trial Registration Clinicaltrials.gov NCT00823407

Impact of prospectively determined A118G polymorphism on treatment response to injectable naltrexone among methamphetamine-dependent patients: an open-label, pilot study.

Objectives:Methamphetamine (MA) addiction has no known effective pharmacotherapy. Small trials showed beneficial effects for oral naltrexone in amphetamine users. Trials in alcohol-dependent subjects showed better response in persons with the A118G single nucleotide polymorphism of the &mgr;-opioid receptor. We conducted a pharmacogenetic trial of sustained release intramuscular naltrexone to examine the role of the A118G single nucleotide polymorphism in MA dependence. Method:All eligible A118G subjects screened were enrolled; an equal number of wild type (A118A) subjects were selected using modified urn randomization, balanced on sex and frequency of recent MA use. Enrolled subjects received a single 380 mg naltrexone injection and weekly psychotherapy for 4 weeks. Self-report of MA use and urine toxicology for MA was assessed twice weekly. Urine samples with less than 1000 ng/mL of MA were considered negative. Results:Eleven A118G and 11 A118A subjects were enrolled. There were no significant differences between the groups in days of abstinence from MA use (11.5 vs 14.8, respectively, P = 0.51), the number of MA-negative urine samples (1.7 vs 1.8, respectively, P = 0.97), consecutive MA-negative urine samples (1.0 vs 1.5, respectively, P = 0.91), or the number of MA-negative urine samples before first relapse (0.9 vs 1.5, respectively, P = 0.86). Conclusions:Although A118G polymorphism has been shown to be associated with improved treatment response to naltrexone among alcoholics, whether this polymorphism impacts naltrexone treatment response among MA users is unclear at this time.

A Method to Quantify Illicit Intake of Drugs from Urine: Methamphetamine

Qualitative urinalysis can verify abstinence of drug misuse but cannot detect changes in drug intake. For drugs with slow elimination, such as methamphetamine (MA), a single episode of abuse can result in up to 5 days of positive urine drug screens. Thus, interventions that produce substantial decreases in drug use but do not achieve almost complete abstinence are classified as ineffective. Using nonpharmacologic doses of deuterium-labeled l-methamphetamine (l-MA-d3) we have developed a simple, robust method that reliably estimates changes in MA intake. Twelve subjects were dosed with 5 mg of l-MA-d3 daily and challenged with 15, 30, and 45 mg of nonlabeled d-MA (d-MA-d0) after reaching plasma steady status of l-MA-d3. Urinary concentration ratios of d-MA-d0 to l-MA-d3 provided clear separation of the administered doses with as little as 15-mg dose increments. Administered doses could not be resolved using d-MA-d0 concentrations alone. In conclusion, the urinary [d-MA-d0]:[l-MA-d3] provides a quantitative, continuous measure of illicit MA exposure. The method reliably detects small, clinically relevant changes in illicit MA intake from random urine specimens, is amenable to deployment in clinical trials, and can be used to quantify patterns of MA abuse.

The Effects of 6β-Naltrexol, a Putative Neutral Opioid Antagonist, in Opioid-Dependent Subjects: A Proof-of-Concept Trial

Potential complications of prescription opioid use include abuse and constipation. 6β-Naltrexol (6βNTX), a neutral opioid antagonist, may alleviate these complications when co-formulated with μ-opioid analgesics. In a double-blind ascending dose study, four subjects on methadone maintenance received 6βNTX (0.05, 0.15, 0.50 and 1.0 mg). 6βNTX was generally well tolerated; three of four subjects reported willingness to take higher doses. Increased gastrointestinal activity was evidenced by decreased oral-cecal transit time and prompt laxation at higher doses.

Imagery Scripts and a Computerized Subtraction Stress Task Both Induce Stress in Methamphetamine Users: A Controlled Laboratory Study

Patients treated for methamphetamine (MA) dependence have a high rate of relapse, and stress is thought to play a key role. We sought to develop a computerized procedure for experimentally inducing stress in MA users. In a within-subjects design, we compared a computerized subtraction stress task (SST) to personalized stress-imagery scripts and a control condition (neutral imagery) in 9 former MA users, recruited in San Francisco in 2006–2007. We assessed blood hormone levels, anxiety and craving for MA on visual analog scales, and the Positive and Negative Affect Schedule and made linear mixed-effects models to analyze the results. Both the SST and stress scripts were effective in inducing self-report markers of stress in MA users. Because the SST is easily reproducible and requires less time of staff and participants, it may be a useful alternative for measuring stress reactivity in drug users.